DE69109514T2 - 4- (4-alkoxyphenyl) -2-butylamine derivatives and their production processes. - Google Patents

Abstract

This invention relates to an optically active (+)-secondary amine of the formula: <CHEM> wherein R<1> is a lower alkyl, and to a process for preparing a useful intermediate for the production of the optically active dopamine derivatives, namely, optically active (+)-primary amine of the formula: <CHEM> wherein R<1> is a lower alkyl, characterized by the reduction of said optically active (+)-secondary amine.

Description

4-(4-Alkoxyphenyl)-2-butylamine derivatives and their preparation processes

The invention relates to a process for the preparation of optically active primary (+)-amines of the formula:

in which R¹ is a lower alkyl radical, which are suitable as intermediates for the preparation of optically active dopamine derivatives (I), e.g. dobutamine. It further relates to key intermediates for the amines and the process therefor.

Dobutamine was developed by Eli Lilli and Company. It has the following formula:

This compound is very useful because it can increase myocardial contractile force without isolating norepinephrine. The racemate, the 1:1 mixture of the d-isomer and l-isomer, is used clinically for patients to treat suddenly decreased myocardial contractile force and shock.

There are two types of optical isomers of dobutamine and the optically active dobutamine was prepared by optical resolution of the intermediate as disclosed in USP 3,987,200.

The invention provides an optically active secondary (+)-amine of the formula:

in which R¹ is a lower alkyl radical,

and a process for producing an optically active primary (+)-amine (I) of the formula:

in which R¹ is a lower alkyl radical,

characterized by the reduction of the optically active secondary (+)-amine. The optically active amine (I) is a very useful intermediate for the preparation of optically active dopamine derivatives.

The d-isomer (hereinafter referred to as d-dobutamine) has been reported to have greater potency as a cardiotropic agent than the l-isomer (hereinafter referred to as l-dobutamine). Therefore, it is desirable to produce only the d-dobutamine.

However, the conventional method is not economical since the optical resolution was applied to the final intermediate for dopamine production, namely the trimethyl ether compound. Of course, a more economical preparation of the desired optically active compound can be achieved by preparing an optically active intermediate at an earlier stage in the series of reactions and applying the subsequent reactions to it.

It has now been found that the reaction of (+ )α-methylbenzylamine with the compound (II) of the formula:

in which R¹ has the meaning given above,

and the subsequent reduction an optically active secondary (+)-amine (III) of the formula:

in which R¹ has the meaning given above, in high yield, and the subsequent reduction of the resulting amine gives a suitable intermediate of d-dobutamine, namely optically active primary (+)-amine (I) of the formula:

in which R¹ has the meaning given above.

As described below, compound (I) is a very important intermediate in the production of d-dobutamine.

In addition, compound (III) is very important as a starting substance for the preparation of compound (I).

In this specification, the lower alkyl group represented by R1 means a C1-C6 alkyl group, e.g. methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and hexyl groups.

Preferably R¹ is a methyl and ethyl group.

This invention is described in detail below.

As an asymmetric synthesis for producing an optically active secondary amine (III) by reacting (+)-α-methylbenzylamine with the compound (II), there are two processes; (A) in a stepwise system, the reduction of the resulting Schiff base with a reduction catalyst, such as nickel catalysts (e.g. Raney nickel), platinum oxide or palladium on activated carbon, preferably with a nickel catalyst under a hydrogen atmosphere, preferably under excess pressure, or (B) the reduction of the Schiff base produced by dehydrogenation condensation with a reduction catalyst, such as nickel catalysts (e.g. Raney nickel), platinum oxide or palladium on activated carbon, preferably with a nickel catalyst, under a hydrogen atmosphere, preferably under excess pressure.

The desired asymmetric synthesis can also be achieved if a metal hydride, such as sodium borohydride, is used.

The reduction may be carried out in an alcohol, e.g. methanol or ethanol, or an ester, e.g. ethyl acetate, under a slight pressure, such as about 1 to about 20 kg/cm², preferably about 3 to about 10 kg/cm². If required, acetic acid may be added.

The reaction time varies with the reaction conditions used, but is from several hours to several days for the process (A) and several tens of hours for the process (B). The reaction system is contaminated with a by-product, i.e. a small amount of diastereomer of the compound (III) upon reduction, but can easily give the desired optically active secondary amine by fractional crystallization from acetone and methanol-ethyl acetate.

The product prepared by reduction can, if necessary, be isolated after conversion to its desired acid addition salt by treatment with an inorganic acid, e.g. hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid.

Condensation is preferably carried out by heating with benzene or toluene with equipment to capture the water formed.

An optically active amine (I) can be prepared by reducing the compound (III) under a hydrogen atmosphere, preferably under excess pressure.

The reaction is carried out by reduction under about 2 to 20 kg/cm² of hydrogen pressure for more than ten hours using a catalyst such as palladium on activated carbon, palladium hydroxide or platinum oxide in an alcohol such as methanol or ethanol.

In another embodiment, the reaction can be carried out with heating for several hours in the presence of ethyl chloroformate.

The invention is explained in more detail by the following examples, but it should be understood that these examples are for illustration only and do not limit the present invention thereto.

Example 1A: Procedure (A)

Preparation of N-(R)-α-methylbenzyl-(1R)-1-methyl-3-(4-methoxyphenyl)-1-propylamine hydrochloride IIIa

A mixture of 13.6 g of 4-(4-methoxyphenyl)-2-butanone IIa, 11.5 g of d-(+)-α-methylbenzylamine and 1 g of Raney nickel (Kawaken Finechemical, NDHT-90) in 90 ml of 98% ethanol is shaken at a primary pressure of 4.85 kg/cm² for 5 days. The catalyst is separated by filtration and the filtrate is concentrated under reduced pressure. The residue is partitioned between dichloromethane and 10% dilute hydrochloric acid. The dichloromethane layer is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 14.9 g of a mixture of diastereomers IIIa and IIIb in the ratio 6.7:1 with a yield of 60.9%. 74% d.e.

Example IB: Procedure (B)

A solution of 1.78 g of 4-(4-methoxyphenyl)-2-butanone and 1.21 g of d-(+)-α-methylbenzylamine in benzene is heated under reflux for 5 hours while removing the resulting water and then the solvent is evaporated under reduced pressure.

The mixture of the resulting residue and 0.3 g of Raney nickel in 10 ml of 98% ethanol is shaken at a primary pressure of 4.5 kg/cm2 for 22 hours. The catalyst is separated by filtration and the filtrate is concentrated under reduced pressure. The residue is partitioned between dichloromethane and 10% hydrochloric acid. The dichloromethane layer is washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.14 g of a mixture of diastereomers IIIa and IIIb in a ratio of 5.8:1 with a yield of 66.9%.

Isolation of diastereomers IIIa and IIIb

To 2.14 g of the mixture prepared in Example IB, 20 ml of acetone are added and the resulting mixture is heated and then left to stand at room temperature for 2 hours. The precipitate (1) (71 mg) is separated by filtration. The solvent of the filtrate is changed to methanol-ethyl acetate (1:4) and the solution is left to stand overnight at room temperature, giving (2) 1.321 g of crystals. The resulting mother liquor was recrystallized successively from acetone and methanol-ethyl acetate (1:4) to give (3) 63 mg and (4) 256 mg of crystals, respectively. Crystals (1) and (3) are compound IIIb and crystals (2) and (4) are IIIa.

Compound IIIa

100% of the

Melting point 157 to 158ºC

[α]D +69.6º (c 1.117, methanol)

IR max(Nujol)2930, 1253cm⊃min;¹

NMR(CDCl3)δ1.51(3H, d, J=7Hz), 1.88(3H, d, J=7Hz), 2.11(2H, m), 2.32(1H, m), 2.72(2H, m), 3.78(3H, s), 4.29(1H, m), 6.75(2H, d, J=9Hz), 6.95(2H, d, J=9Hz), 7.34(3H, m), 7.54(2H, m), 9.64(1H, m), 10.00(1H, m).

Anal. calcd. (%) for C₁₉H₂₆ClNO: C, 71.34; H, 8.19; Cl, 11.08; N, 4.38; Found (%): C, 71.30; H, 8.16; Cl, 11.11; N, 4.47.

Compound IIIb

Melting point 257 to 258ºC

[α]D -3.4º, [α]₃₆₋₅ -18.1º(c 0.976, 24 ºC, methanol)

IR max(Nujol) 2950, 2930, 1240cm⊃min;¹

NMR(CDCl3)δ: 1.35(3H, d, J=6Hz), 1.82 (3H, d, J=7Hz), 1.8 2.1(1H, m), 2.3 2.6(3H), 2.35(1H, m), 3.70(3H, s), 4.29(1H, m), 6.66(2H, d, J=7Hz), 6.94(2H, d, J=9Hz), 7.39(3 H), 7.62(2H), 9.51(1H, m), 10.04(1H, m).

Anal. calcd. (%) for C₁₇H₂₆ClNO: C, 71.34; H, 8.19; Cl, 11.08; N, 4.38; Found (%): C, 71.14; H, 8.15; Cl, 10.79; N, 4.40

Example 2 (+)-(R)-1-methyl-3-(4-methoxyphenyl)-1-propylamine Ia

A suspension of 3.20 g of hydrochloride IIIa in ethyl acetate is shaken with an aqueous solution of sodium hydrogen carbonate. The organic layer is separated and the aqueous layer extracted with ethyl acetate. The combined organic layer is washed once with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is dissolved in 40 ml of ethanol and 0.8 g of 20% palladium hydroxide on activated carbon (Pearlman catalyst) is added. The mixture is shaken at a hydrogen pressure of 4.15 kg/cm² for 20 hours. The catalyst is separated by filtration and the mother liquor is then concentrated under reduced pressure to give 1.68 g of the title compound.

NMR(CDCl3)δ1.11(3H, d, J=6HZ), 1.5 1.7(4H, m), 2.62(2H, m), 2.91(1H, m), 3.78(3H, s), 6.82(2H, d, J=7Hz), 7.11(2H, d, J=8HZ).

Hydrochloride of Ia: mp 124 - 125ºC

[α]D +7.0º, [α]₃₆₅+23.6º(c 1.029, 24 ºC, methanol)

IR max(Nujol): 3500, 3350, 1513, 1244cm-1.

NMR(CD3OD)δ: 1.33(3H, d, J=7Hz), 1.87(2H, m), 2.65(2H, m), 3.25(1H, m), 3.76(3H,s), 6.85(2H, d, J=9Hz), 7.14(2H, d, J=8HZ).

Anal. calcd. (%) for C₁₁H₁₈ClNO.O.2H₂O : C, 60.24; H, 8.46; Cl, 16.16; N, 6.39; Found (%): C, 60.40; H, 8.49; Cl, 16.38; N, 6.66.

Anti-IIIb (1.11 g), namely the enantiomer of IIIb, prepared by reacting 1-α-methylbenzylamine as in Example IA is reacted in the same way as in Example 2 to give 0.53 g of the hydrochloride Ia in 85.2% yield.

Example 3

d-(+)-α-Methylbenzylamine and compound IIa are reacted by the procedure in Example IA under the conditions shown in Table 1 to give compound IIIa. The results are also shown in Table 1. Table 1 Catalyst Hydrogen pressure [kg/cm²] Reaction time Reaction temp. Solvent Produced ratio IIIa : IIIb Raney nickel Platinum oxide Ethanol Methanol-acetic acid

Example 4

d-(+)-α-Methylbenzylamine and compound IIa are reacted by the procedure in Example IB under the conditions shown in Table 2 to give compound IIIa. The results are also shown in Table 2. Table 2 Catalyst or reducing agent Hydrogen pressure [kg/cm²] Reaction time Reaction temperature Solvent Prepared ratio IIIa : IIIb Sodium borohydride Ethyl acetate Methanol RT. Room temperature

In the following reference example, the preparation of d-dobutamine from optically active primary amine Ia is shown.

Reference example 1 (1) Preparation of (-)-(R)-2-(3,4-dimethoxyphenyl)-N- (4-methoxyphenyl-1-methyl-n-propyl)acetamide 4

To a solution of 2.08 g of 3,4-dimethoxyphenylacetic acid in 22 ml of dichloromethane is added 0.86 ml of thionyl chloride. After the mixture has been heated under reflux for 1 hour, the reaction mixture is concentrated to half its volume under reduced pressure.

5 ml of triethylamine are added to 20 ml of a suspension of 1.90 g of hydrochloride Ia in dichloromethane under ice cooling. The mixture is stirred at room temperature until the solid disappears. The solution of the acid chloride prepared above is added dropwise to the resulting solution under ice cooling. The mixture is left to stand overnight at room temperature, then washed with water and dried over anhydrous sodium sulfate and the solvent is evaporated under reduced pressure. The residue is recrystallized from ethyl acetate:ether to give 2.48 g of the title compound in 78.8% yield.

Melting point 116 - 117ºC

[α]D -31.2º (c 1.057, 24 ºC, CHCl₃)

IR max(Nujol): 3290, 1638, 1514, 1230 cm-1.

NMR(CDCl3)δ: 1.09(3H, d, J=7Hz), 1.63(2H, m), 2.49(2H, t, J=8HZ), 3.49(2H, s), 3.78(3H) s), 3.87(3H, s), 3.89(3H, s), 4.01(1H, m), 5.19(1H, d, J=8Hz), 6.73 6.9(5H), 7.0 2(2H, d, J=9Hz).

Anal. calcd. (%) for C₂₁₁H₂₇NO₄: C, 70.56; H, 7.61; N, 3.92; Found (%): C, 70.59; H, 7.66; N, 3.99.

(2) Preparation of (+ )-(R)-3,4-dimethoxy-N-[3-(4-methoxyphenyl)-1-methyl-n-propyl]-2-phenylethylamine hydrochloride 5

To a solution of 1.92 g of amide 4 and 1.01 g of sodium borohydride in 22 ml of dioxane is added dropwise a solution of 1.61 g of glacial acetic acid in 5 ml of dioxane and the mixture is heated under reflux for 18 hours. Ice water is added to the reaction mixture, which is then extracted with chloroform. The extract is washed once with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is crystallized from ether to give 1.30 g of the title compound in 63.7% yield.

Melting point 144 - 146ºC

[α]D +9.8º(c 0.997, 25ºC, methanol),

[α]₃₆₅ +35.4º(c 0.997, 25ºC, methanol),

IR max(Nujol)1516, 1246 cm⊃min;¹

NMR(CDCl3)δ 1.48(3H, d, J=6Hz), 2.21(2H, m), 2.35(1H, m), 2.55(2H, m), 2.63(2H, m), 3.15(4H), 3.72(3H, s) , 3.83(3H, s), 3.85 (3 H, s), 6.7-6.85(5H), 7.0(2H, d, J=9Hz).

Anal. calcd. (%) for C₂₁₁H₃�0ClNO₃: C, 66.39; H, 7.96; Cl, 9.33; N, 3.69; Found (%): C, 65.67; H, 8.04; Cl, 9.07; N, 3.96.

(3) Preparation of (+ )-(R)-3,4-dihydroxy-N-[3-(4-hydroxyphenyl)-1-methyl-n-propyl]-2-phenylethylamine hydrochloride 6

A solution of 364 mg of the above-mentioned trimethoxy compound 5 in dichloromethane is shaken with a 10% aqueous solution of sodium hydroxide. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated to give 312 mg of the free amine.

A solution of this free amine in 9.5 ml glacial acetic acid and 37 ml 48 % hydrobromic acid is incubated for 4 hours under Heated to reflux. The reaction mixture is evaporated to dryness under reduced pressure.

To the residue, 15 ml of 4 N hydrochloric acid is added and the mixture is heated, and then the reaction mixture is treated with activated carbon. The resulting mixture is left overnight at room temperature to obtain 203 mg of colorless prismatic crystals in 62.7% yield.

Melting point 201 - 203ºC

[α]D +10.8º (c 0.930, 24ºC, methanol)

[α]D +39.5º (c 0.930, 24ºC, methanol)

IR max(Nujol): 3310, 1516cm-1.

NMR(CD3OD)δ 1.36(3H, d, J=7Hz), 1.79(1H, m), 2.04(1H, m), 2.45 2.95(4H), 3.10 3.30(3H), 6.57(1H, dd, J=8.2Hz), 6.65 6.80 (4H), 7.04(2H, d, J=8Hz).

Anal. calcd. (%) for C₁₈H₂₄ClNO₃: C, 63.99; H, 7.16; Cl, 10.49; N, 4.15; Found (%): C, 63.92; H, 7.22; Cl, 10.78; N, 4.22.

Claims (4)

for the Contracting States: AT BE CH DE DK FR GB GR IT LI LU NL SE 1. Optically active secondary (+)-amine of the formula: in which R¹ is a lower alkyl radical or an acid addition salt thereof. 2. A process for the preparation of an optically active secondary (+)-amine according to claim 1, characterized by the reaction of (+)-α-methylbenzylamine with a compound of the formula: in which R¹ has the meaning given above, followed by the reduction of the resulting compound and optionally subsequent salt production. 3. Process according to claim 2, which is carried out by reductive amidation. 4. Process for the preparation of an optically active primary (+)-amine of the formula: in which R¹ has the meaning given above, characterized by the reduction of an optically active secondary (+)-amine of the formula: in which R¹ has the meaning given above.